Genetics and Progression of Early-onset Substance Dependence and HIV Risk

描述(申请人提供)：本申请中提出的研究旨在了解促进停止或继续使用有问题的物质以及从青春期开始的相关高危行为的遗传和环境因素。我们建议对一个受到严重影响的青少年样本进行~12年(最初6年随访后)的随访，因为他们正在过渡到成年；这是一个关键的发展时期，我们预计这些人中的一部分将减少或停止有问题的物质使用和相关的高风险行为，而其他人将坚持最严重、最具破坏性的行为，导致极高的发病率和死亡率。我们的中心目标是了解描绘这些生命轨迹的遗传和环境因素。我们的纵向研究结果表明，青少年首发的药物使用者在青春期主要表现出对大麻、尼古丁和酒精的滥用和依赖，五年后他们的药物使用的严重性有所进展。作为年轻人，他们报告了极高的终生可卡因(29.2%)、苯丙胺(29.2%)和鸦片类药物(10.8%)使用障碍以及与艾滋病毒/艾滋病相关的危险行为，如注射吸毒(11%)和危险的性行为。事实上，与社区样本相比，这些人报告的终身性伴侣数量是前者的两倍多，无保护措施性行为的比率高出33%。此外，他们表现出令人震惊的成人监禁率(55%)和过早死亡率(2.6%)。这项建议扩展了我们在青少年药物依赖遗传流行病学方面的多重PI合作。这三个具体目标是：1)确定先证者和兄弟姐妹从青春期到成年期的药物使用、反社会和艾滋病毒危险行为的不同发展轨迹。A)测试青少年的初始特征，如性别、早发性物质使用障碍(SODS)和品行障碍(CD)的严重程度，以及预测这些轨迹的神经认知功能(例如，去抑制) 以及b)测试成人资源，如肥胖症的治疗、住房稳定性、职业稳定性和社会支持是否与这些轨迹相关。2)确定药物使用障碍、反社会和艾滋病毒危险行为发展轨迹的遗传和环境架构。A)测试社会背景，如社会经济地位、刑事司法参与、药物滥用治疗/自助参与和应激性生活事件在改变遗传影响方面的调节作用，以及b)测试调节效应是否在不同的发展阶段(青春期、青春期和成年期)有所不同。3)测试共同或特定病因学影响对整个发育阶段的肥胖症、反社会行为和艾滋病毒危险行为的影响。

DESCRIPTION (provided by applicant): The research proposed in this application aims to understand genetic and environmental factors that promote desistance or continuation of problematic substance use and associated high-risk behaviors that began in adolescence. We propose an ~12-year follow-up (6 years after an initial 6-year follow-up) of an extremely affected adolescent sample as they transition into adulthood; this is a critical developmental period when we expect a portion of these individuals to decrease or desist problematic substance use and associated high-risk behaviors, while others will persist with the most serious, destructive behaviors leading to devastatingly high rates of morbidity and mortality. Our central goal is to understand the genetic and environmental factors that delineate these life trajectories. Results from our longitudinal research demonstrate that adolescent-onset substance users, who primarily exhibited abuse of and dependence on marijuana, nicotine, and alcohol during adolescence, progressed in the severity of their substance use five years later. As young adults, they report dramatically high rates of lifetime cocaine (29.2%), amphetamine (29.2%), and opiate (10.8%) use disorders as well as HIV/AIDS-related risk behaviors such as injection drug use (11%) and risky sexual behaviors. Indeed, when compared with community samples, these individuals report more than twice the number of lifetime sexual partners and a 33% higher rate of unprotected sex. Furthermore, they exhibit alarming rates of adult incarceration (55%) and early death (2.6%). This proposal extends our multiple-PI collaboration focused on the genetic epidemiology of adolescent-onset drug dependence. The three specific aims are to: 1) Identify distinct developmental trajectories of substance use, antisocial, and HIV risk behaviors in probands and siblings from adolescence to adulthood. a) Test initial characteristics of the adolescents, such as sex, severity of early onset substance use disorders (SUDs) and conduct disorder (CD), and neurocognitive functioning (e.g., disinhibition) that predict these trajectories and b) Test whether adult resources such as treatment for SUDs, housing stability, occupational stability, and social support are associated with these trajectories. 2) Determine the genetic and environmental architecture of developmental trajectories of substance use disorders, antisocial and HIV risk behaviors. a) Test the moderating role of social context, such as SES, criminal justice involvement, substance abuse treatment/self-help involvement, and stressful life events, in altering genetic influence and b) Test whether moderating effects vary across developmental periods (adolescence, young adulthood, and adulthood). 3) Test the influence of shared versus specific etiologic influences on measures of SUDs, antisocial behaviors, and HIV risk behaviors across development.